17beta-hydroxy-androstane-[3, 2-b]-thiazole and derivatives thereof



United States Patent "Ofifice 3,080,359 Patented Mar. 5, 1963 The present invention relates to novel cyclopentanophenanthrene compounds and process of preparing same. I More particularly the invention relates to novel thiazolesteroid compounds and more specifically to novel derivatives of the androstane series in which a thiazole moiety is fused to the androstane nucleus. The androstane nucleus may contain an aliphatic hydrocarbon at C-17oc, a methyl or a fluorine group at G4 or (3-6, a keto or hydroxyl group at C-11 and a halogen such as fluorine or chlorine at C-9a. The androstane nucleus may also contain unnsaturation at C-4, and/or at C-6, 7, in which case a methyl group may be present at 0-4 or at C-6 or a halogen such as fluorine, chlorine or bromine at (3-4.

The novel compounds of the present invention are hormones of the androgenic type having favorable anabolic, anti-gonadotrophic and anti-estrogenic activity and may be illustrated by the following formulas:

In the above formulas, R represents hydrogen or methyl; R represents hydrogen or the acyl residue of a hydrocarbon carboxylic acid having less than 12 carbon atoms, saturated or unsaturated, straight chain or branched chain aliphatic, cyclic, cyclic aliphatic, aromatic and may be substituted by functional groups such as hydroxyl, acyloxy of up to 12 carbon atoms, alkoxy of up to 8 carbon atoms, amino or halogen; R represents hydrogen or an aliphatic hydrocarbon, saturated or unsaturated, containing up to eight carbon atoms; R represents hydrogen, lower allcoxy, aryloxy, aliphatic hydrocarbon, saturated or unsaturated, containing up to 8 carbon atoms, aryl or araliphatic containing up to 12 carbon atoms, which may or may not contain substituents such as alkoxy, hydroxy, methylenedioxy or dihydroxy groups; R represents hydrogen, methyl, fluorine, chlorine or bromine; R represents hydrogen or methyl; Y represents hydrogen, keto or fl-hydroxy; X represents hydrogen and when Y and R are other than hydrogen, X represents hydrogen, fluorine or chlorine. X represents hydrogen or methyl; X" represents hydrogen or fluorine and when X and Y are hydrogen, X" may also be methyl. Z indicates a double bond or a saturated linkage between C-6 and C-7.

Typical ester groups at C-17fl include the acetate, propionate, butyrate, hemisuccinate, enanthate, caproate, benzoate, phenoxyacetate, trimethylacetate, aminoacetate, cyclopentylpropionate and B-chloropropionate.

Typical aliphatic hydrocarbon groups at C-l7u are methyl, ethyl, propyl, butyl, vinyl, l-propenyl, Z-butenyl, ethinyl and l-butinyl.

Typical groups at position 2 are methyl, ethyl, propyl, phenyl, p-methoxyphenyl, p-ethoXy-phenyl, 3,4-methylenedioxyphenyl, 3,4-dihydroxyphenyl, phenoxy and ethoxy.

The following equation illustrates in .part a method for preparing the novel compounds of the present invention:

In the above formulas R, R R R X, Y and Z have the same meaning as set forth previously. Z indicates a double bond or a saturated linkage between C-4 and C-5.

In practicing the process above outlined a Z-hydroxymethylene-testosterone or a 2-hydroxymethylene-dihydroallotestosterone is reacted with a slight excess of a molar equivalent of bromine in a solvent such as methanol or tertiary butanol and in the presence of sodium or potassium acetate at a temperature below C. The thus formed 2-bromo-2-aldehydo-compound is refluxed with a dilute methanolic solution of sodium methoxide for a short period of time to form the Za-bIOmO derivative. After condensation of the latter with a thioformamide or a substituted thioformamide such as thioacetamide, ethylthioacetamide, thiobenzamide, phenylthioacetamide, xanthogenam-ide or phenoxythioacetarnide in a solvent such as ethanol for approximately eight hours, followed by dilution with water and extraction with a solvent such as ether or ethyl acetate, there is finally obtained the thiazolesteroid.

Alternatively, androstane compounds having no unsaturated bond capable of being brominated, can be formed directly by reacting the androstane compound with one molar equivalent of bromine in acetic acid to form the 2a-bromo compound which is then condensed with a thioatmide in the same manner as set forth above.

This latter process may be illustrated -by the following equation:

bromine acetic acid him Example I A solution of 1 g. of dihydroallotestosterone in 50 cc. of acetic acid was treated with a few drops of a saturated solution of hydrogen bromide in acetic acid and then with 1.1 molar equivalents of bromine'dissolved in acetic acid, containing 1.1 molar equivalents of sodium acetate, little by little, with stirring and maintaining the temperature below 20 C. After complete decolorization, the mixture was kept for half an hour at room temperature, poured into ice water and the 2a-bromo-dihydroallotestosterone was collected by filtration, washed with water and dried under vacuum.

A solution of '1 g. of 2u-bromo-dihydroallotestosterone in 25 cc. of ethanol was refluxed with 2 g. of thioformamide for 8 hours. It was then concentrated to a small volume under reduced pressure, diluted with water and extracted with ethyl acetate. Aqueous sodium hydroxide v solution was added to the aqueous phase until it was strongly alkaline and again extracted with ethyl acetate.

This extract was washed several times with water, dried over anhydrous sodium sulfate and evaporated. Recrystallization of the residue from acetone-hexane afforded 17,8-hydroxy-androstane-[3,2-b1- thiazole.

Example 11 By following the method described in the preceding example, 17a-methyl-dihydroallotestosterone was converted into 2a-bromo-l7u-methyl-dihydroallotestosterone and finally into l7a-methyl-l7,8-hydroxy-androstan-[3,2- b]-thiazole.

Example III By following the method described in Example I, but using as starting steroid the acetate of 2a-bromo-17umethyl-19-nor-dihydroallotestosterone, there was obtained 17a-methyl-1713-acetoxy-19-nor-audrostane-[3,2-b] thiazole.

Example 1V By following the method described in Example 1, 6afluoro-l7a-methyldihydroallotestosterone, 6a-fluoro-17aethyl-dihydroallotestosterone and the corresponding 19- nor derivatives thereof were converted into 6oz-flLIOIO-17otmethyl-17fi-hydroxy-androstan-[3,2-b] thiazole; 6a-fluoro- 17a-ethyl-17a-hydroxy-androstan-[3,2-b] -thiazole; Got-fluor-o-l7a-methyl-17 8-hydroxy-19-nor-androstan [3,2-b]- thiazole and 6ec-fiuoro-17a-ethyl-l7fl-hydroxy-l9-nor-androstan-[3,2-b1-thiazole.

Example V By following the method .described in Example I, there were obtained 9u-fluoro-17a-methyl-115,175 dihydroxyandrostan- [3 ,2-b] -thiazole, 9a-fiuoro-1 7a-methy1-1 l-ketol7fl-hydroxy-androstan-[3,2-b]-thiazole and Hot-methyl- 11B,17B-dihydroxy-androstan-[3,2-b] thiazole from flllOl'O-17OL-H'l6thYl-1 lfi-hydroxy dihydroallotestosterone, 9a-fiuoro-17a-methyl-1l-keto-dihydroallotestosterone and 17a-methyl-11fi-hydroxy dihydroallotestosterone respectively.

Example VI By substituting in the methods of the preceding examples thioacetamide for thioformamide there was obtained 17B-hydroxy-androstane- 2'-methyl-[3,2-b]-thiazole; 17amethyl-17p-hydroxy-androstane-2-methyl-[3,2 b] thiazole; 17a-methyl-17/3-acetoxy-l9-nor-androstane-2'-methyl-[3,2-b]-thiazole; Got-fluoro-17a-methyl-17fl-hydroxy-androstane-2'-methyl-[3,2-b]-thiazole; 6a-fluoro-17u ethyl- 17B-hydroxy-androstane-2-methyl-[3,2-b] thiazole; 6afluoro-l7a-methyl-17B-hydroxy-19 nor androstane 2- methyl-[3,2-b]-thiazole; 6u-fiuoro-l7a-ethyl-17fi-hydroxy- 19-nor-androstane-2'-methyl-[3,2-b] -thiazole; 9a fluoro- 17 a-methyl-l 1,6,17fi-dihydroxy-androstane-Z-methy1-[3,2- bJ-thiazole, 9u-fiuoro-17a-methyl-1l-keto hydroxyandrostan'Z-methyl-(3,2-b) thiazole and 17oc-methy1-11fi, 17,8-dihydroxy-androstan-2-methyl-[3,2-b]-thiazole.

By substituting in the methods of Examples I-V, thiobenzamide for thioformamide, there were obtained the corresponding compounds having a phenyl group at position 2'.

Example VII In the methods of Examples I-V, there was substituted the thioformamide by xanthogenamide to produce finally the corresponding compounds having an ethoxy group at position 2'.

Example VIII A mixture of 1 g. of Z-hydroxymethylene-testosterone, 13 cc. of methanol and 0.4 g. of potassium acetate was treated with 1.1 molar equivalents of bromine dissolved in 2 cc. of carbon tetrachloride, with stirring, in the course of 50 minutes and maintaining the temperature below 15 C. There was then added 2 cc. of 2 N methanolic solution of sodium methoxide and the mixture was refluxed for 10 minutes, at the end of which the solvent was evaporated under reduced pressure, diluted Example IX In accordance with the method described in the preceding example, 2-hydroxymethylene-1 l-keto 17 a methyltestosterone and 2-hydroxy-methylene-11,8-hydroxy -17 xethyl-testosterone were converted into the corresponding 2a-br-omo-derivatives and by condensation with thioform amide were finally converted into 17a-rnethyl-11-keto- 175-hydroxy-A -androstene-[3,2-b]-thiazole and l7a-ethyl- 11p,17/3-dihydroxy-A -androstene-[3,2-b1-thiazole.

Example X A solution of 2-hydroxymethylen-e-testosterone in 50 cc. of t-butanol was treated with 1.1 molar equivalents of sodium methoxide and then little by little with 1.1 molar equivalents of bromine dissolved in 2 cc. of carbon tetrachloride under stirring, in the course of 1 hour and at temperatures below C. The mixture was then stirred at room temperature until decolorization and the solvent was evaporated under reduced pressure; there was thus obtained 2-bromo-2-aldehydo-testosterone. The latter was dissolved in 10 cc. of a 2 N solution of sodium methoxide, refluxed for 10 minutes and cooled, water was added, the mixture was extracted with ether and the extract was washed with water to neutral, dried over anhydrous sodium sulfate and the ether was evaporated. There was thus obtained Za-bromO-testosterone, which upon reaction with thioformamide in the manner described in Example I afforded 17 B-hydroxy-n -andr-ostene- [3,2-b1-thiazole, identical with the compound obtained in Example VIII.

The com-pounds listed under A were treated with ethyl formate and sodium hydride in the manner described by Ringold et al., J. Am. Chem. Soc. 81, 427 (1959) and in U.S. Patent 2,908,693 to introduce a hydroxymethylene group at 02. The thus formed Z-hydroxymethylene derivatives of the compounds listed under A were in turn converted into the thiazole [3,2-b1-derivatives of the compounds listed under B by following the method described in Examples VIII or X:

Example XX By following the method described in Example I, 4&- methyl-di-hydroallotestosterone, 17oz ethyl-dihydroallotestosterone and 6a-methyl-dihydroallotestosterone were converted into 40; methyl 175 hydroxy-androstane- [3,2-'b]-thiazole, 17oz ethyl 1713 hydroxyandrostane- [3,2-b1-thiazole and 6a-methyl-17B-hydroxy-androstane- [3 ,2-b] -thiazole.

Example XXI 175 acetoxy dihydr-oallotestosterone and 17p propionoxy-dihydroallotestosterone were transformed into the corresponding 2a-bromo compounds by employing the method described in Example I, and by further treatment with thioformarnide, as described in such example, were further converted into 17B-acetoxy-androstane- [3,2-b1-thiazole and 175-propionoxyandrostane-[3,2-b]- thiazole.

Example XXII A mixture of 3 g. of 17ct-ethinyl-17fl-hydroxy-19-norandrostane-[3,2-b]-thiazole produced in Example XIV, cc. of anhydrous benzene, 15 cc. of acetic anhydride and 1 g. of p-toluenesulfonic acid was stirred at room temperature for 24 hours and diluted with water; the organic layer was separated, washed with water, 5% sodium carbonate solution and again with water to neutral, dried over anhydrous sodium sulfate and evaporated. Recrystallization of the residue from acetone-hexane afforded the acetate of 17a-ethinyl-17fi-hydroxy-19-norandrostane- [3 ,2-b-] -thiazole.

Example XXIII Soc. 81-, 427 (1959) ltO introduce a hydroxymethylene group at C-2.

Example XXIV In accordance with the method described in Example VIII, 2 hydroxymethylene 17a methyl 4 chloro- 9d-fluoro-1l-keto-testosterone and Z-hydroxymethyleri- 17a-methy1-4-bromo-9u-fluoro1l-keto-testosterone were transformed into the corresponding Za-bromo derivatives and finally into 17a-methyl 4-chloro-9a-fluoro-11-keto- 17,8 hydroxy A androstene [3,2-b] thiazole and into 17a methyl 4 bromo 9oz fiuoro 11 keto- 17(3-hydroxy-A -androstene-[3,2-h]-thiazole.

The starting materials were formed by treating 17amethyl-A -androstadien-17,B-ol-3-one with hydrogen peroxide in the presence of aqueous sodium hydroxide soluton. The thus formed 17u-methyl-4fl,5/8-oxido- A -androsten-17,8-ol-3-one was reacted with concentrated hydrochloric or hydrobromic acid in acetone solution to give the 17u-methyl-4-(chloro or bromo)-A androstadien-17fi-ol-3-one, which in turn was treated with hypobromous acid to produce 17a-methyl-4-(chloro or bromo) 9u-bromo-A -androsten-1 15,17fl-diol-3-one. By reaction of the latter compounds with potassium acetate in methanol solution, there was formed the 17a-methyl- 4-(chloro or bromo)-9 8,1lfi-oxido-A -androsten-1713-01-3- yone; The epoxide ring was then opened by reaction with anhydrous hydrofluoric acid to form the corresponding halohydrin. By oxidation of the llfl-hydroxyl group as by reaction with chromic acid in aqueous acetic acid, there was formed the corresponding 17a-methyl-4-(ch1oro or bromo)-9o-fiuor0-1l-keto-testosterone which upon reaction with ethyl formate and sodium hydride as described by Ringold et al., supra, there was introduced a Z-hydroxymethylene group at C-2.

7 Example XXV By following the method described by Ringold et al., I. Am. Chem. Soc. 81, 427 (1959), 6a-fluoro-ll 8-hydroxy-dihydroallo-testosterone was reacted with ethyl formate and sodium hydride to form the corresponding 2-hydroxymethylene derivative, which in turn was converted into the thiazole [3,2-b] derivative in accordance with the method described in Example I.

The 6a-fluoro-11,8-hydroxy-dihydroallotestosterone was obtained from the hydrogenation of a solution of 3.0 g-

of 6a-fiuoro-1lfl-hydroxy-testosterone in 100 cc. of methanol containing a palladium on charcoal catalyst. After one mole of hydrogen had been absorbed, the catalyst was removed by filtration, the methanol was evaporated to thus furnish a mixture of the 5m and 5,8 isomers of 6a-fluoro-11f3 hydroxy dihydrotestosterone which was separated by chromatography on neutral alumina.

Example XXVI By substituting for the thioformamide thioacetamide or xanthogenamide in the method of Examples VIII through XXI, XXIII, XXIV and XXV there were pro- .duced the corresponding compounds having a methyl or ethoxy substituent at position 2'. I

Example XXVII By substituting for the thioformamide thiobenzamide in the procedure of Examples VIII through XXV, there were produced the corresponding compounds having a phenyl substituent at position 2.

Example XX VIII Upon treatment with acetic anhydride in benzene solution and in the presence of p-toluenebenzenesulfouic acid, there was prepared the 17B-acetate of the products formed in Examples 11 through VII, IX, XIII, XVI, XIX, XXIH, XXIV and of the l7ot-ethyl-17fl-hydroxy-androstane-[3,2-b]-thiazole produced in Example XX.

In a similar manner, there was also produced other esters such as the propionate, enanthate and benzoate of all of the compounds formed in such examples.

We claim:

1. A compound of the following formula:

XI wherein X' is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon containing up to 8 carbon atoms; and R is selected from the group consisting of hydrogen, an aliphatic hydrocarbon group containing up to 8 carbon wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogenand an aliphatic hydrocarbon containing up to 8 carbon atoms; R is selected from the group consisting of hydrogen, an aliphatic hydrocarbon group containing up to 8 carbon atoms, an aryl group, an aralkyl group containing up to 12 carbon atoms, lower alkoxy and lower alkoxy aryl containing up to 12 carbon atoms; Y is selected from the group consisting of keto and ,B-hydroxy; and X and X are selected from the group consisting of hydrogen and fluorine.

5. 9oz fiuoro 17a methyl 115,175 dihydroxyandrostane-[3,2-b]-thiazole.

6. 60a fluoro 115,175 dihydroxy androstane [3,2- b]thiazole.

7. A compound of the following formula:

wherein R is selected from the group consisting of methyl and fluorine; R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon containing up to 8 carbon atoms; and R is selected from the group consisting of hydrogen, an aliphatic hydrocarbon group containing up to 8 carbon atoms, an aryl group, an aralkyl group containing up to 12 carbon atoms, lower alkoxy and lower alkoxy aryl containing up to 12 carbon atoms.

8. 6oz fiuoro 17a methyl 17,8 hydroxy androstane- 3,2-b] -thiazole.

9. 6a methyl 17p acetoxy androstane [3,2 b]- thiazole.

10. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon containing up to 8 carbon atoms; R is selected from the group consisting of hydrogen, an aliphatic hydrocarbon group containing up to 8 carbon atoms, an aryl group, an aralkyl group containing up to 12 carbon atoms, lower alkoxy and lower alkoxy aryl containing up to 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, fluorine, chlorine and bromine; and Z is selected from the group consisting of a double bond, between 06 and C-7 and a saturated linkage between 06 and C-7.

11. 4,170: dimethyl 175 acetoxy A androstene- [3,2-b1-thiazole.

12. 4 fluoro 17,8 hydroxy A androstene 2'- methyl- 3,2-b] -thiazole.

13. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon containing up to 8 carbon atoms; R is selected from the group consisting of hydrogen, an aliphatic hydrocarbon group containing up to 8 carbon atoms, an aryl group, an aralkyl group containing up to 12 carbon atoms, lower alkoxy and lower alkoxy aryl containing up to 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, fluorine, chlorine and bromine; X is selected from the group consisting of hydrogen and fluorine; Y is selected from the group consisting of keto and ,B-hydroxy and Z is selected from the group consisting of a double bond between (3-6 and C-7 and a saturated linkage between 06 and C-7.

14. 17c! methyl 90c fluoro 11,43,175 dihydroxy- M-androstene- 3,2-b] -thiazole.

15. 11 keto 17,8 hydroxy 13 androstadiene 2'- methyl- 3,2-b -thiazole.

16. A compound of the following formula:

wherein R is selected from the group consisting of hy drogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen and an wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboXylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon containing up to 8 carbon atoms; R is selected from the group consisting of hydrogen, an aliphatic hydrocarbon group containing up to 8 carbon atoms, an aryl group, an aralkyl group containing up to 12 carbon atoms, lower alkoXy and lower alkoxy aryl containing up to 12 carbon atoms; X is selected from the group consisting of hydrogen and fluorine; Y is selected from the group consisting of keto and fl-hydroxy.

19. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon containing up to 8 carbon atoms; and R is selected from the group consisting of hydrogen, an aliphatic hydrocarbon group containing up to 8 carbon atoms, an aryl group, an aralkyl group containing up to 12 carbon atoms, lower alkoxy and lower alkoxy aryl containing up to 12 carbon atoms.

20. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R is selected from the group consisting of hydrogen and an aliphatic hydrocarbon containing up to 8 carbon atoms; R is selected from the group consisting of hydrogen, an aliphatic hydrocarbon group containing up to 8 carbon atoms, an aryl group, an aralkyl group containing up to 12 carbon atoms, lower alkoxy and lower alkoxy aryl 12 containing up to 12 carbon atoms; X is selected from the group consisting of hydrogen, fluorine and chlorine; and Y is selected from the group consisting of keto and ,s-hydroxy.

References Cited in the file of this patent UNITED STATES PATENTS 2,813,859 Korman Nov. 19, 1957 

1. A COMPOUND OF THE FOLLOWING FORMULA: 